[unreadable] The E23K polymorphism in KCNJ11 (the gene that encodes the islet ATP-dependent potassium channel Kir6.2, the target for sulfonylurea medications) and common variants in the gene that encodes the transcription factor 7-like 2 (TCF7L2) have been robustly associated with type 2 diabetes. These variants have detectable effects on quantitative glycemic traits. For example, homozygotes for the K allele at KCNJ11 E23K have decreased insulin secretion during the first 30 minutes of an oral glucose tolerance test (OGTT), as measured by the insulin to glucose ratio (IGR). [unreadable] Given these findings, we hypothesize that variants in genes that are reproducibly associated with type 2 diabetes may impact the effect of anti-diabetic medications. In particular, sulfonylureas may have differential effects on individuals depending on the allelic variant they carry at KCNJ11 E23K; conversely, because TCF7L2 is postulated to influence insulin secretion by regulating levels of glucagon-like peptide 1 (GLP-1), and sulfonylureas act at a more distal step in the insulin secretion pathway, the effect of sulfonylureas on insulin secretion should be independent of genetic variation at TCF7L2. Preliminary evidence also suggests a metformin x genotype interaction. [unreadable] We therefore propose to examine 1) the acute response to a sulfonylurea challenge (glipizide 5 mg orally) in 750 subjects at risk of diabetes or with early diabetes (on diet treatment alone), depending on genotype at KCNJ11 E23K and TCF7L2 rs7903146; 2) the acute response to short-term metformin treatment on the insulin sensitivity index in the same group, depending on genotype at KCNJ11 E23K; and 3) acute insulin secretion (by IGR derived from an OGTT) and GLP-1 levels after short-term metformin treatment (500 mg bid x 4 doses) in the same group of subjects, depending on genotype at TCF7L2 rs7903146. [unreadable] In order to maximize statistical power and ensure a timely completion of this project, this proposal intends to perform two simple outpatient measurements in a single major referral center, with the help of a diverse team of established clinical investigators who have an interest and expertise in metabolic traits. If successful, this proposal should help clarify the pathophysiologic mechanisms by which these key genetic variants increase risk of type 2 diabetes, and assess their impact on commonly used antidiabetic treatments. In addition, this pilot study will lay the groundwork for a long-term, outcomes-based pharmacogenetic clinical trial. [unreadable] [unreadable]